Nanoscale electronic devices have the potential to achieve exquisite sensitivity as sensors for the detection of soluble antigens and the immune response to those antigens. Our laboratories have focused on the design and development of nanomaterials to achieve this purpose. For example, the Reed laboratory has developed a semiconductor solid-state technology using CMOS (complementary metal-oxide-semiconductor)-FET (field effect transistor) technology, a critical step in system-scale integration of these sensors into standard electronics. These devices are amenable to chemical surface modification and are highly sensitive to bound molecular charge, enabling rapid, label-free detection (within seconds) of femtomolar concentrations of DNA and proteins in solution. In addition, these new devices enable sensing of stimulus induced extracellular acidification of a minute number of cells in microliter volumes. The Fahmy laboratory is focused on the application of novel biomaterials to detection and modulation of the immune response. Here, this combination of experience will be focused on the optimization and testing of these nanosensors as a diagnostic for detection of antigens, antibodies and antigen-responsive lymphocytes. Our application aims to demonstrate the utility of this technology for cancer diagnostic applications. Our working hypothesis is that nanoscale CMOS wires can be developed as rapid, quantitative diagnostic devices of soluble antigens as well as the immune response to those antigens. To test this hypothesis, we propose to: 1) Fabricate integrated semiconducting nanosensors incorporating on-chip fluidics for high throughput sampling capability. 2) Optimize chemical surface modification of these sensors for ligand binding, and test the limits of sensitivity of the sensor for detection of cancer markers and production of vaccine-mediated antibodies. 3) Demonstrate the utility of this system in the detection of antigen- specific lymphocyte responses and tumor-associated vaccine response. Because the strength of the approach lies in a novel fabrication scheme of nanowires and seamless integration with CMOS technology, our approach facilitates wide use in basic and diagnostic clinical settings requiring sensitive and high-throughput screening of samples. Relevance Statement: We have developed a novel technology to synthesizing nanowires (NWs) allowing their direct integration with microelectronic systems for the first time, as well as their ability to act as highly sensitive biomolecule detectors that could revolutionize biological diagnostic applications. Our proposed work outlines a research plan for the development of the next generation portable electronic nanosensor and demonstrates its application in the read-out of cancer biomarkers and the immune response. These nanosensors can replace current technology with a powerful solid-state device useful for rapid diagnosis in clinical settings.